tbuckley/cabot-search huggingface dataset:
Identifying anatomopathological factors associated with a Oncotype DX 21-gene recurrence score higher than 25 in menopaused women.
Authors: Clara Guerif, Mathieu Jamelot, Fatima Kebir, Sonia Zilberman, Lauren Seknazi, Xavier Barthere, Louise De Forceville, Claire Theodore, Cyril Touboul, David Buob, Joseph Gligorov, Marc Antoine Benderra
Journal: Journal of Clinical Oncology (2023)

e15156 Background: Oncotype DX recurrence score is a predictive assay clinically used to estimate the risk of distant recurrence for patients with hormone receptor positive (HR+) early breast cancer (EBC) and to predict the benefit of adjuvant chemotherapy, based on molecular factors of the tumor itself. This retrospective study examines the factors that are linked to a Recurrent score (RS) higher than 25, indicating adjuvant chemotherapy for menopaused women with hormone receptor positive early breast cancer. Methods: 157 patients diagnosed with HR+, HER 2 negative early breast cancer who underwent Oncotype DX testing during their treatment between November 2018 and December 2022 were included in the study. Of these 157 patients, 114 were older than 50 years old and with complete data. Univariate and multivariate logistic regression analysis were used to select pathological factors associated with a RS higher than 25. The receiver operating characteristic (ROC) curve was used to assess the optimal threshold of Estrogen receptor (ER), Progesterone receptor (RP) and Ki67. Results: Median age was 65 years (IQR: 59-71). 57 patients (47.5%) had a T1 tumor and 48% of patients had negative lymph nodes. Most of the patients had a Scarff-Bloom-Richardson (SBR) grade 1 (12%) or grade 2 tumor (70%), and 18% of the patients had grade 3 breast cancer. The cell proliferation marker Ki67 was higher than 30 % for 28 patients (23%). The RS was higher than 25 for 17 patients out of 120 patients. Multivariate logistic regression analysis showed that Ki67 higher than 30% was significant associated with RS &gt; 25 (p = 0.01). To predict a RS &gt; 25, the optimal threshold were respectively 80% for the PR, 90% for the ER and 30% for the Ki67. The area under the ROC curve (AUC) were respectively 0.70, 0.60 and 0.88. With the threshold of 30% for Ki67, the sensitivity was 0.76 and specificity 0.89. Conclusions: The use of the Oncotype DX test is validated and useful to better decide the absence of chemotherapy indication in adjuvant situation in some patients with HR+ cancers. However, access to it remains difficult and expensive in some countries with limited resources. Ki67 and SBR grade could be used as an indication for adjuvant chemotherapy but cannot replace Oncotype DX.
Association of albumin and neutrophil-to-lymphocyte ratio with hormone-mediated depression in prostate cancer.
Authors: Martha M. Kato, Constanza Martinez, Maria Currier
Journal: Journal of Clinical Oncology (2023)

e24214 Background: Androgen deprivation therapy (ADT) increases the risk of developing depression which can affect quality of life and adherence to treatment. Depression has been associated to inflammation in patients with cancer. Albumin and neutrophil-to-lymphocyte ratio (NLR) are inflammatory biomarkers that to our knowledge have not been evaluated in hormone mediated depression in prostate cancer (PC). The aim of this study is to evaluate the severity of hormone related depression and its association with inflammatory biomarkers, demographics, and cancer treatment variables and to determine antidepressant treatment response. Methods: A retrospective chart review of consecutive referrals to psycho-oncology of PC patients on ADT with new onset depression was conducted. Demographics, cancer and psychiatric history, and laboratories within 1 week of initial visit were collected. Assessments for depression included clinical interview and patient-rated scale [Beck Depression Inventory (BDI)]. These measures were done at baseline (before starting an antidepressant) and follow-up to determine treatment response. Successful antidepressant treatment response is defined as ≥50% reduction in baseline BDI score. Statistical analysis comparing the association of clinical variables between depression, inflammatory biomarkers, and demographics included Pearson’s correlation, chi-square, ANOVA, t-test, and binary logistic regression was used to determine associations with depression. Data was dichotomized using median split for inflammatory biomarkers due to skewness. Results: A sample of 26 PC patients on leuprolide (mean age 70 years; 13 Hispanic, 13 non-Hispanic) included 13 with mild depression (BDI£20) and 13 with moderate- to-severe depression (BDI&gt;20). Moderate-to-severe depression was associated with higher NLR (≥3, p= .041), stage IV PC (n=15, p= .001), and Hispanics ( p= .033). Lower albumin (£3.9) was associated with higher age ( p= .007), higher NLR ( p= .006), and non-Hispanics ( p= .049) but not depression. Over 54% (13/24) of patients did not respond to antidepressant treatment. In logistic regression only NLR and Stage IV PC remained significantly associated with depression after adjusting for confounding variables. Conclusions: NLR and stage IV PC were both associated with moderate-to-severe depression. These results are likely due to increased level of inflammation in advanced cancer. Inflammation has been associated with treatment resistant depression which could explain why 54% of patients did not respond to antidepressant treatment. NLR is an inexpensive routinely used test in cancer centers that has the potential to be used as a biomarker of severity of depression in PC patients.
Long-term follow-up results of ipilimumab and nivolumab for the treatment of mismatch repair deficient locally advanced rectal cancer.
Authors: Danny Trotier, Nataliya Volodymyrivna Uboha, Kristina A. Matkowskyj, Wei Zhang, Jeremy D. Kratz, Evie Carchman, Eilse Lawson, Cristina Sanger, Charles Heise, Sam Joseph Lubner, Monica Arun Patel, Noelle K. LoConte, Michael F. Bassetti, Dustin A. Deming
Journal: Journal of Clinical Oncology (2023)

e15652 Background: Mismatch repair deficient (dMMR) colorectal cancers have unique biology and responses to therapy. In the advanced setting, first line immunotherapy has superior activity compared to chemotherapy. Recent studies have demonstrated improved responses with neoadjuvant anti-PD1 therapy for dMMR locally advanced rectal cancer (LARC). In this study, we review our experience with the combination of ipilimumab (ipi) and nivolumab (nivo) for the treatment of dMMR LARC. Methods: Patients (pts) with dMMR LARC treated with ipi/nivo at the University of Wisconsin Carbone Center were identified under an IRB-approved protocol. Baseline demographics, molecular testing, treatment history, clinical imaging, and pathological evaluations were collected and summarized. Pts were followed with serial imaging (CT/MRI), endoscopic evaluations, and ctDNA MRD assays. Results: Fours pts (median age: 63 [range: 59-68]; 50% female) with dMMR LARC treated with ipi/nivo were identified. 3 pts had T4 tumors and were node positive. 1 patient had a mutation in MSH6, 1 patient had 2 mutations in MSH2, another had loss of MLH1/PMS2 on IHC, and the last patient had loss of MSH2/MSH6 on IHC. None of the patients have known germline variants. 2 patients were treated initially with FOLFOX chemotherapy and had progressive disease prior to conversion to ipi/nivo. Median follow-up is 25.5 months [range: 9-42] and 1 pt continues on nivo treatment. Pts were treated with 1-4 infusions of ipi and 2-24 months of nivolumab. All patients achieved a complete clinical/pathologic response and remain without evidence of disease recurrence. None of the pts required additional surgery or radiation therapy for cancer recurrence/progression. 3 of the 4 patients developed grade 3/4 immune-related adverse events, including 2 patients with adrenal insufficiency and 1 patient with immune hepatitis. 1 pt developed a fibrotic stricture at the site of the prior cancer requiring resection. Conclusions: dMMR LARC is a unique subtype of rectal cancer sensitive to combination immunotherapy with high potential for complete responses and organ preservation. The use of ipi/nivo in this cohort of pts resulted in complete pathogenic responses for all that remain durable over an extended period of time, though with increased immune-related adverse events compared to anti-PD1 therapies alone. This regimen is currently being studied further in prospective studies.
Proteome analysis of patients with early onset colorectal cancer in Ireland.
Authors: Mary O Reilly, Aleksandar Kristic, Catherine Murphy, Anna Linehan, Kieran Wynne, Kieran Sheahan, Des C Winter, Ray McDermott, Walter Kolch
Journal: Journal of Clinical Oncology (2023)

e15639 Background: Early onset colorectal cancer (EOCRC) is defined as colorectal cancer (CRC) in those under the age of 50. The incidence of EOCRC is rising at an alarming rate. Unlike in the USA, screening for CRC in Ireland begins at 60 years of age. It has been hypothesized that the signatures of CRC in younger populations could differ from that in elderly patients. Deep characterization of the tissue using omics profiling, including proteomics, could provide the answer to this question. Moreover, omics profiling could identify new biomarkers for patient stratification and earlier diagnosis. Methods: Forty micrograms of healthy and matched frozen tumors were taken from 8 patients with locally advanced EOCRC for whole proteome analysis. The samples were digested with trypsin and mass spectrometry was performed using data dependent analysis parallel accumulation serial fragmentation (DDA-PASEF). The raw data was searched against the Homo sapiens subset of the Uniprot Swissprot database (reviewed) with the proteomics pipeline software Fragpipe (Version 19.1) Statistical analysis was performed using Perseus software. Results: When we compared proteomes of 8 tumor tissues versus matched normal tissues, out of 5,717 protein IDs, there were more than 1,300 differentially expressed proteins. Our pathway enrichment analysis, using differentially expressed proteins, has identified a number of molecular functions altered in EOCRC samples. The most enriched signaling pathways were associated with FAT10 signaling, neutrophil extracellular trap (NET) signaling and oxidative stress response. The upstream regulator analysis (URA) has identified LASP1 and LONP1 proteins. LASP1 is known to promote CRC progression via the Hippo signaling pathway, while LONP1 is known to play a role in mitochondrial functions, metabolism, and epithelial–mesenchymal transition (EMT) in CRC cells. Importantly, the NET signaling activation in all samples suggests unfavorable immunomodulation that could stimulate cell proliferation and invasiveness. The observed activation of oxidative stress signaling components is in line with the inflammatory nature of CRC, which could signify potential response to immune checkpoint inhibitors. Conclusions: Our findings in a small cohort of patients indicate that proteomics can provide a deeper insight into aberrant signalling in EOCRC. We have identified novel vulnerabilities that might be used as therapeutic targets as well as patient stratification biomarkers. Additional proteome studies with corresponding genomic and transcriptomic analysis are needed to fully understand the potential of this approach.
Phase I/II study of nab-paclitaxel combined with S-1 as adjuvant chemotherapy in diffuse type of stage III gastric or gastroesophageal junction adenocarcinoma.
Authors: Yuehong Cui, Jia Wei, Yiyi Yu, Bei Xu, Jing Wu, Xiaojing Xu, Tianshu Liu
Journal: Journal of Clinical Oncology (2023)

e16064 Background: Diffuse type (Lauren's classification) of gastric adenocarcinoma (GAC) or gastroesophageal junction adenocarcinoma (GEJ) has a poorer prognosis than intestinal type of GAC or GEJ. Studies have shown that nab-paclitaxel combined with S-1 has a synergistic anti-tumor effect on advanced gastric cancer. We designed this trial to evaluate the efficacy and safety of nab-paclitaxel plus S-1 as adjuvant chemotherapy in diffuse type of stage III GAC or GEJ. Methods: This study was a multi-center, open-label, phase I/II study. The results of the phase I dose escalation study have already been reported, and the recommended phase II dose (RP2D) of nab-paclitaxel is 260mg/m 2 . Patients with stage III diffuse type GAC or GEJ after D2 dissection and achieved R0 resection were included in this study. S-1 monotherapy was used as adjuvant therapy in the first cycle. If absence of grade3/4 treatment-related adverse events (AEs) of S-1 monotherapy, nab-paclitaxel (260mg/m 2 , d1, q3w) and S-1 [body surface area (BSA) &lt;1.25 m 2 , 80mg/d; BSA 1.25–1.5 m 2 , 100mg/d; BSA &gt;1.5 m 2 , 120mg/d; d1-14, q3w] were administered for 6 cycles. Then patients still received S-1 monotherapy for 8 cycles. In phase II study, the primary endpoint was 1-year disease free survival (DFS) rate, and the secondary endpoints were 3-year DFS rate and safety. Results: From January 2021 to February 2023, a total of 42 patients were enrolled in this analysis (3 patients in nab-paclitaxel 260mg/m 2 dose group in phase I and 39 patients in phase II). The median age (range) was 53 (29~69) years, 18 patients (42.86%) were stage IIIA, 10 patients (23.81%) were stage IIIB and 14 patients (33.33%) were stage IIIC. The median follow-up time was 13.26 months. As of January 2023, 12 patients experienced recurrence. The 1-year-DFS rate was 74.07%, median DFS and 3-year-DFS rate were not reached. The incidence of adverse effects (AEs) was 78.57% (33/42), and the rate of grade 3-4 AEs was 42.86% (18/42). The most common AEs were neutropenia and leukopenia. In addition, we performed next generation sequencing (NGS) for 5 relapsed patients, and 5 non-relapsed patients who were matched to the relapsed patients. The results showed that the mutant rates of tumor supressor gene CDH1, ARID1A, KMT2D, and TP53 in non-relapsed patients were higher than that in relapsed patients. The positive rate of ctDNA were 60% in relapsed patients, but no ctDNA was detected in non-relapsed patients. Conclusions: Adjuvant chemotherapy with nab-paclitaxel and S-1 followed by S-1 monotherapy exhibited promising clinical efficacy, with acceptable tolerability. This study deserves further investigation and follow up for diffuse type of GAC or GEJ. Clinical trial information: NCT03977220 .
BL-B01D1, a first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC), in patients with locally advanced or metastatic solid tumor: Results from a first-in-human phase 1 study.
Authors: Li Zhang, Yuxiang Ma, Yuanyuan Zhao, Wenfeng Fang, Hongyun Zhao, Yan Huang, Yunpeng Yang, Likun Chen, Xue Hou, Wen Zou, Muran Ding, Jing Yu, Suoyu Zhang, Junxian Wang, Sa Xiao, Hongwei Wang, Hai Zhu, Martin Sebastian Olivo, Yi Zhu
Journal: Journal of Clinical Oncology (2023)

3001 Background: BL-B01D1 is a first-in-class novel ADC consisting of an EGFRxHER3 bispecific antibody linked to a novel TOP-I inhibitor payload via a cleavable linker. We now present safety/efficacy results from a FIH phase I study of BL-B01D1. Methods: This study included patients (pts) with locally advanced or metastatic solid tumors. For dose escalation (D-ESC, i3+3), BL-B01D1 was administered intravenously at doses of 0.27, 1.5, 3.0 mg/kg QW, 2.5, 3.0, 3.5mg/kg D1D8 Q3W or 4.5, 5.0, 6.0 mg/kg D1 Q3W. A subset of pts were enrolled into dose-expansion (D-EXP) at Q3W regimens. Results: As of Dec 31, 2022, 150 pts were enrolled and received at least one dose (D-ESC, n=25; D-EXP, n=125). DLTs were neutropenia, febrile neutropenia and thrombocytopenia at 3.0mg/kg QW and 3.5mg/kg D1D8 Q3W. The MTDs were determined to be 3.0mg/kg D1D8 Q3W and 6.0mg/kg D1 Q3W. D-EXP was carried out at 2.5, 3.0mg/kg D1D8 Q3W and 4.5, 5.0, 6.0 mg/kg D1 Q3W. 144 pts were enrolled across all Q3W dose levels (D-ESC and D-EXP), including 89 NSCLC, 7 SCLC, 27 nasopharyngeal cancer (NPC), 19 HNSCC and 2 others. Most common TRAEs (&gt;10%, all grade / ≥ G3) were leukopenia (60%/30%), neutropenia (51%/34%), anemia (45%/15%), thrombocytopenia (44%/19%), alopecia (30%/0%), nausea (29%/&lt;1%), vomiting (28%/0%), asthenia (21%/&lt;1%), decreased appetite (22%/&lt;1%), asthenia (21%/&lt;1%), hypophagia (16%/0%), diarrhoea (15%/2%), mouth ulceration (15%/&lt;1%), rash (13%/0%). No ILD was observed. 122 pts were evaluable for efficacy (at least 1 tumor assessment). PK and other details will be updated in the meeting. Conclusions: BL-B01D1 demonstrated encouraging efficacy in heavily pretreated metastatic/locally advanced solid tumors, especially in pts with EGFRm NSCLC. The safety profile showed adequate safety and tolerability. Clinical trial information: NCT05194982 . [Table: see text]
Interim update of the ATRC-101 phase 1b trial in advanced solid tumors.
Authors: Bartosz Chmielowski, Saravut John Weroha, Susanna Varkey Ulahannan, Deborah Blythe Doroshow, Frances Valdes, Tanios S. Bekaii-Saab, John D. Powderly, Alejandro Recio-Boiles, Jordan Berlin, Yan Xing, Sudha Khurana, Philippe Bishop, Steven J. Isakoff, Benjamin Adam Weinberg
Journal: Journal of Clinical Oncology (2023)

2505 Background: ATRC-101 monoclonal antibody targets tumor-specific ribonucleoprotein complex (RNP) and elicits anti-tumor immunity, innate and adaptive, in preclinical models. Methods: Phase 1b is evaluating ATRC-101 as monotherapy, every 3 (3M) or 2 (2M) weeks (wk), and ATRC-101 in combination with pembrolizumab (3P) in participants (pts) with advanced solid tumors. ATRC-101 target expression is determined by CAP-CLIA IHC assay. For pts described herein, pre-treatment (tx) tumor biopsies were assessed for target expression by IHC retrospectively or prospectively. Enrollment in 3M and 3P is currently open to pts who are target positive (RNP+ve) by IHC with an H-score ≥ 50. Objectives are safety (primary), PK, immunogenicity, recommended dose for expansion, activity by RECIST1.1 and biomarker analyses in pre-tx and on-tx tumors. Results: As of Nov 18 th , 2022, 67 pts received ≥1 dose of ATRC-101 (median prior tx 5, range 1-12). Tumor types were colorectal (CRC, 28), ovarian (10), breast (9), melanoma (8), non-small cell lung (NSCLC, 6), head and neck squamous cell (3), urothelial (1), esophageal (1) and small bowel (1). Tx emergent adverse events (TEAEs) Grade ≥3 occurred in 22 (33%) pts and were related to ATRC-101 in 2 (3%). No tx discontinuations or dose reductions related to ATRC-101. RECIST1.1 best overall responses in efficacy evaluable 61 pts included 1 complete response (CR) in RNP+ve melanoma (3P, 10mg/kg), and 1 partial response (PR) in RNP+ve NSCLC (3M, 30mg/kg). Further, disease stabilized (SD) in 24 pts (39%) and 35 pts had disease progression (PD, 57%) with evidence of association between anti-tumor activity and target expression. Of 24 SD, 22 were in monotherapy cohorts and included 9 CRC pts with highly refractory disease. Conclusions: ATRC-101 alone and in combination with pembrolizumab continues to be well tolerated with evidence of anti-tumor activity. Interim data support ongoing enrollment of pts with RNP+ve pre-tx tumors. Updated and new data including durability of disease control will be presented. Clinical trial information: NCT04244552 . [Table: see text]
Molecular profiling of Chinese patients with advanced hepatocellular carcinoma using circulating tumor DNA.
Authors: Jianjiao Zhu, Mingwei Li, Xiaoxue Ma, Jiayue Qin, Shanbo Cao
Journal: Journal of Clinical Oncology (2023)

e16186 Background: Hepatocellular carcinoma (HCC) has limited treatment options. Molecular analysis of its mutational landscape may enable the identification of novel therapies. Noninvasive strategies are critical to HCC given the challenge of obtaining liver tissue biopsies. Recent studies show that circulating tumor DNA (ctDNA) can reflect tumor genomic profiles. Thus, we aimed to analyze the molecular characteristics of HCC using ctDNA. Methods: A total of 308 plasma samples and 32 matched tumor tissues from Chinese patients with hepatocellular carcinoma (n = 308) were analyzed by Acornmed panel with 808 cancer-related genes. Results: A total of 4984 somatic variations were identified in 96.1% (296/308) ctDNA, including 4202 single nucleotide variants, 772 copy number variations and 10 fusions, and the median blood tumor mutation burden (bTMB) was 4.36 mut/Mb. Alterations in TP53 (152/308, 49.4%) were the most prominent variation, followed by those in TERT (48/308, 15.6%), ARID1A (37/308, 12.0%), CTNNB1 (34/308, 11.0%), NF1 (16/308, 7.7%), BRAF (16/308, 7.7%), PTEN (22/308, 7.1%) and EGFR (19/308, 6.2%). Interestingly, in MET and MYC, amplifications occurred more frequently than mutations. Moreover, we systematically evaluated clinically actionable mutations and totals of 587 potential drug-related targets from 211 patients (68.5%) were identified. In addition, in 32 patients with matched tumor tissues and plasma samples, sequencing detected alterations in 96.9% (31/32) tumor tissue DNA (tDNA) and 100% (32/32) ctDNA, respectively. Further analysis found that 25.4% of mutations of tissues were founded in ctDNA and 32.5% of mutations of ctDNA were detected in tissues. Among them, 68.8% (22/32) patients had at least one overlapping variant called by tDNA and ctDNA. The most common shared mutation was TP53 (8/32, 25.0%), followed by PTEN (2/32, 6.3%) and ARID1A (2/32, 6.3%). Meanwhile, two shared copy number variants were detected in two patients (6.3%), respectively. Conclusions: This study contributes to the understanding of the molecular characteristics of HCC using ctDNA and suggests potential clinical utility for this technology. Furthermore, it can more comprehensively reflect the molecular mutation status of patients by combining tissue and ctDNA detection.
A single-institution analysis of a rare variant of pancreatic neoplasm-osteoclastic giant cell tumor.
Authors: Meghana Kesireddy, Samia Asif, Robin High, Fang Yu, Mridula Krishnan
Journal: Journal of Clinical Oncology (2023)

e16315 Background: Pancreatic osteoclastic giant cell tumor (OGCT) is a rare variant (&lt;1% cases) of pancreatic neoplasm. Due to its rarity, prospective studies on management are limited. The prognosis and molecular characteristics may differ from pancreatic adenocarcinoma. Methods: We analyzed demographics, clinical features, treatment modalities, and outcomes of overall survival (OS) and progression-free survival (PFS) in patients with pancreatic OGCT at our institution from 2005-2022. Results: We identified 8 OGCT patients with a median age of 67, of whom 7 had locoregional disease (resectable- 5, borderline resectable- 1, locally advanced-1), and 1 had denovo metastatic disease at diagnosis. The borderline resectable and locally advanced patients eventually developed metastatic disease. The majority of patients were male (n=5), Caucasian (n=7), former smokers (n=5), had no significant alcohol use (n=8) and had no pre-existing pancreatitis (n=8). 4 of the 5 resectable patients had surgery, and 2 received adjuvant chemotherapy. The median OS was 54 months for locoregional disease (n=5) vs.16 months for metastatic disease (denovo metastatic and progression to metastatic disease, n=3). The median OS was 54 months for surgical resection (n=4) vs. 25 months for those without surgical resection (n=4) based on quartile computations from the Kaplan-Meier survival curve. Conclusions: Our patients had a longer OS than the previously reported OS of less than 12 months for all stages of pancreatic OGCT. There was no progression in resectable patients, indicating an indolent disease with an overall good prognosis. Patients with locoregional disease or those who underwent surgical resection had longer OS, but due to the small sample size and censored patient survival times (i.e., patients still alive), the statistical significance of this trend could not be calculated. Studies are required to understand tumor biology and determine the optimal multidisciplinary treatment. [Table: see text]